The prevalence of type 2 diabetes is growing worldwide, with an estimated 250 million people afflicted with the disease by the year 2020. It is clear that insulin resistance plays a major role in the development of type 2 diabetes, and recent studies suggest that resistance to insulin is primarily caused by a defect in glucose transport. GLUT4 is the main insulin-responsive glucose transporter. Despite its importance, the regulation of GLUT4 expression remains incompletely understood. KLF15 is a novel member of the Kruppel-like family of DNA-binding proteins that is highly expressed in adipose and muscle tissue. Overexpression of KLF15 in adipocytes results in increased expression of GLUT4 and increased glucose uptake. KLF15 and MEF2A, a known activator of GLUT4, synergistically transactivate the GLUT4 promoter. The first goal of these studies is to define the mechanism of induction of GLUT4 by KLF15. Structure-function analysis will be used to identify the region(s) of KLF15 which are responsible for GLUT4 induction. Furthermore, we will also explore how KLF15 and MEF2A cooperate to maximally induce GLUT4 expression. The second goal is to understand the role of KLF15 in vivo. Mice deficient in KLF15 have been generated and initial assessment of these animals indicates that the level of GLUT4 in both adipose and skeletal muscle tissue is decreased. Paradoxically, these mice also exhibit substantial fasting hypoglycemia. The basis for the inability of KLF15 knockout mice to maintain glucose homeostasis will be studied by assessing glucose uptake into tissues, serum metabolite and hormone levels, the synthesis/degradation and tissue content of glycogen and triglycerides, and the expression of genes in the gluconeogenic pathway. The results of these studies may lead to the development of novel therapeutic strategies for the treatment of diabetes. The candidate's long-term goals are to establish an independent laboratory studying insulin resistance states such as diabetes. The studies in this proposal will be performed in an outstanding research environment at the Brigham and Women's Hospital, Harvard Medical School. Support for this proposal will allow the candidate to interact with leading investigators in the field, to intensively study glucose and lipid metabolism, and to establish an independent research career.